Dipropylacetamido-2-pyrimidine in compositions and methods for inducing sedation or tranquilization

ABSTRACT

2-DIPROPYLACETAMIDO PYRIMIDINE IS DESCRIBED AS A TRANQUILIZING AGENT.

United States Patent Int. 01. Ai61k 27/00 US. Cl. 424-251 5 Claims ABSTRACT OF THE DISCLOSURE 2-dipropylacetamido pyrimidine is described as a tranquilizing agent.

CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of our copending application Ser. No. 675,063 filed Oct. 13, 1967, now abandoned.

SUMMARY OF THE INVENTION This invention relates to compositions and methods for inducing tranquilization and/or sedation in mammals and for potentiating tranquilization or sedation in such animals. More particularly the invention relates to pharmaceutical compositions containing dipropylacetamidopyrimidine and to methods of inducing tranquilization and/or sedation with said compound.

It is an object of the present invention to provide a new medicament, particularly a compound having tranquilizing properties, namely, dipropylacetamido pyrimidine. It is a derivative of the ester of dipropylacetic acid and 2-amino pyrimidine and hereafter is designated B.46.65.

The product which is the object of the invention can be administered orally in the form of wafers, compressed tablets, sugar-coated pills, capsules, diluted with the usual and convenient excipients according to the desired pharmaceutical form, and in doses of 100 to 1,000 mg. per unit. More generally, it can be administered by all convenient modes (orally, rectally, parenterally or otherwise), in the presence of customary excipients necessary for the preparation of the selected form of administration.

DETAILED DESCRIPTION OF INVENTION The following examples are presented in order to disclose the invention more fully. It should be understood,

however, that they are not intended to limit the invention in any way.

PROCESS OF PREPARATION For the preparation of the compound of the invention one can proceed in two dilferent ways: either in the absence of solvent, or in the presence of pyridine. In either case the final product obtained gives the same melting point, the same infrared spectrum and a similar spot in thin layer chromatography; thus, it is the same product.

EXAMPLE I In the process of synthesis without solvent, one can utilize, as starting materials, 2 moles of 2-amino py- 3,558,781 Patented Jan. 26, 1971 rimidine and 1 mole of dipropylacetic acid chloride. The reaction can be represented by the following equation:

AdsorbentAluminu m oxide G of Merck EluentChloroform-acetone 8 2 Developer-Iodine vapor The melting point is 101 C. after recrystallization.

The analysis of the amide corresponding to the formula C H ON gives the following results:

Calculated (percent): C, 65.15; H, 8.6; N, 19.0. Found (percent): C, 65.08;H, 8.65; N, 19.01.

Also, the amide that is the object of the invention is characterized by making infrared spectra of Z-amino pyrimidine, of dipropylacetic acid and of product A, in chloroform. The spectrum of product A is different from those of the two others in that it presents:

(a) The peaks for CH CH CH in the zone of 2800 cm.- to 300 cmr which are due to the grouping OH 03417 (b) The peak of 3,400 cm.- which corresponds to H (c) The peaks at 1,700 cm.- and 1,670 cm." due to (d) The large absorption peak typical of pyrimidine from 715 cm. to 800 cmf On the other hand, the peaks of 3,450 cmr and 1,610 cm.- of NH of the Z-amino pyrimidine no longer exist.

The obtained product A is therefore the following amide:

fore, in both cases it is the same amide. The yield is 60% of the theoretical yield.

EXAMPLE II Pharmacological tests For all the pharmacological tests, an oily solution of 200 mg./ml. of B.46.65 in olive oil has been used for TABLE I Average time Average time sleep Average to return to condition, duration sleep condition, Duration of Products, lots of mice minutes of sleep minutes 2nd sleep Controls (Nembutal only) l 17 51 min 346.65 and Nembutal 12 2 hrs, min 10 23 min. Meprobamate and Nembutal 12 3 hrs., 28 min 3 12 1 hr., 12 min.

1 4 animals did not fall asleep. 2 1 animal only fell asleep again. 3 5 animals fell asleep again.

TABLE II Average time Average time sleep Average to return to condition, duration sleep condition, Duration of Products, lots or 10 mice minutes of sleep minutes 2nd sleep Controls (Chloral only) 0 0 B.46.65 and Chloral 3 5 hrs., 49 min 1 1 23 min 1 Only 1 animal fell asleep again.

intraperitoneal injections. For controls or products of reference the minor tranquilizer Meprobamate and the major tranquilizer Chlorpromazine have been used.

(1) Toxicity The acute toxicity, LD determined on the mouse, intraperitoneally, by utilizing the method of Karber and Behrens is 821 mg./kg. The LD in the same conditions for Meprobamate is in the area of 550 mg./kg.

(2) Hypnotic properties The HD calculated by the method of Karber and Behrens is 298 mg./kg. In the same conditions, the HD of Meprobamate is about 215 mg./ kg.

(3) Potentiating action Tests to determine the potentiating action of B.46.65 have been carried out with Nembutal and with Chloral by proceeding in the following manner:

(A) With Nembutal 50 mg./kg. of B.46.65 in oily solution is injected, intraperitoneally, into lots of 10 mice, a quarter of an hour before injecting, subcutaneously, 50 mg./kg. of Nem- (4) Tranquilizing properties been carried a battery of (A) Flight test This test permits the determination of the explorative possibilities of the animals. One uses a plywood parallelepiped box without a top into which descends an inclined plane, also of plywood, covered with a fine mesh. This plane has a horizontal reference line two centimeters beneath the level where it is supported 0n the edge of the enclosure. The assembly is placed in an artificially lighted room away from all intense noise. A sortie of a mouse constitutes a complete crossing of the reference line in the upward direction. The animals are introduced by groups of four and are kept at the bottom of the enclosure for 10 seconds by a small, removable board. For each mouse, one notes the time to the first sortie and the total number of sorties per minute for five minutes. This is also done under the effect of Meprobamate. The results of this test are recorded in Table III.

TABLE 111 Time Average of Average No. of sortles completed inof first total Lots of 32 animals sortie 1 min. 2 min. 3 min. 4 min. 5 min. sorties Controls 22 1. 62 1. 78 1. 15 1.06 1. 09 6. 72 13.46.65, 150 mg./kg 2'22 0. 28 0.31 0. 37 0.31 0.12 1. 4 3 B.46.65, 100 mg./kg 33 1. 59 1. 37 0. 75 0. 0. 56 4. 93 13.46.65, 50 rug/kg 2 1. 5 1.09 0. 84 0.68 6.12 Meprobamate, 150 rug/kg. 0. 51 O. 77 0. 68 1.06 0. 97 3. 9t) Meprobanrate, 100 rug/kg. 1. 37 1. 84 2. 06 2. 25 2. 22 1).

butal in aqueous solution. One measures the time it takes to fall asleep and also the time of sleeping. On awakening, the animals receive, intraperitoneally, a new dose of 50 mtg/kg. of B.46.65, and one measure the speed and the duration of an eventual sleeping condition. The action of the product is compared to that of Meprobamate tested in the same conditions at the doseof mg./kg., I.P.

(B) With Chloral Lots of 10 mice receive 50 mg./kg. of B.46.65 in oily solution, LR, and a quarter of an hour later, 320 mg./kg. of Chloral in aqueous solution at 30 mg./ml. As in the Thus, one notes a very superior effectiveness in comparrson with Meprobamate.

(B) Test of the board with hole board and one notes the number of times it inserts its The results obtained are summarized in Table VII in head in a hole. The number of holes explored is recorded which the figures in the last four columns indicate the at the end of 1, 2, 3, 4 and minutes. percentage of mice incapable of effecting a recovery in The results of this test are in Table IV. less than seconds.

TABLE IV Average N0. of holes explored in Average No.

Lots of 25 animals 1min. 2min. 3min. 4min. 5min. e plo i'e ti Controls 6. 84 5.16 4. 92 4. 88 4. 60 26. 4

13.46.65, 100 mg./kg 6.33 4. 22 4. 70 3.81 3. 66 22. 7

13.46.65, 150 mgjkg 3. 76 3. 48 3. 48 2. 32 2. 52 14. 08 Meprobamate, 150 ingJkg 2. 80 2. l6 2. 32 2. 32 2. 32 12. 4

(C) The chimney test This test permits the appreciation of two groups of TAB LE VII Time elapsed since the injection factors: (1) Neuromus-cular factors (muscular force, Products. D0895, g y, coordination of movements); and Psychic lots of 10 mice lug/kg. 0 min. 30 min. 60 min. 90 min. factors (curiosity, fright, instinct of flight). Controls 0 0 0 0 It consists of introducing mice successively, head first 34655 8 38 t8 28 into a cylinder 30 cm. long and calibrated as a function 0 100 of the size of the mouse, so that by a lateral movement backwards they can leave in less than 30 seconds. The

(F) Test of swimming percentage of animals incapable of carrying out this performance is noted. Meprobamate and Chlorpromazine are This test demonstrates the survival time of tranquiltested under the same conditions comparatively with ized mice in comparison with control mice when the B.46.65. The results of this test are reported in Table V. animals are plunged into a tank filled with water at 16 C. The figures in the columns 10 min., min., 60 min., The control mice drown much more quickly because they correspond to the percentage of mice that have are maddened, moving in an unrestrained manner and failed the test, that is to say, that have not succeeded in quickly tiring themselves. The results of this test are sumleaving the cylinder in less than 30 seconds. marized in Table VIII.

TABLE V D Time elapsed since the injection Products, lots of 10 animals rug/kg. 10min. 30 min. 60min. 90min. 120 min.

Controls 0 0 0 0 0 B.46.65 so 50 50 40 B.46.65 so so so so Me r0bamate so 100 100 60 Ch orpromazine 100 100 100 90 I TABLE VIII (D) Test of the turning shaft Time at This test of equilibration determines the aptitude of the p the e ature of of wh ch animals to coordinate their movements. It consists of 0 Doses, the the mm determining the time during which mice hold their own Water d n on a wooden cylinder of 4.8 cm. diameter turning at a Products, lots of 10 mice; speed of 4 revolutions per minute. The cylinder has a 001M015 0 Gil 13.46.65 i5oI.P-- 16 1 9'3" slightly rough surface so that the animals do not slide Cd: E 50 (5) Action on the central nervous system and The results obtained are summarized in Table VI in neuroplegic properties which the figures in columns 10 min., 30 min., 60 min., correspond to the percentage of animals that The efiect on the central nervous system is determined have failed the test, that is to say, to the percentage of with the aid of the following tests:

mice who have not held on for at least two minutes on the 55 A Test of waltzin mice cylinder after three tries. g

The LP. injection of an aqueous solution of iminodi- TABLE VI Time elapsed after the injection Doses Products, lots of 10 animals rug/kg. 10 min. 30 min. 60 min. 90 min. min.

0 0 0 0 0 0 100I.P. 0 2O 0 0 0 I.P 70 20 20 0 U 200 I.P 100 40 0 0 0 Meprobamate 150 LP 60 100 100 80 60 propionitrile (I.D.P.N.) in the following sequence and (E) Test of tracnon doses: 1 g./kg. the first day; 1 g./kg. the second day; This test demonstrates the functions of equilibration 70 nothing the third y and 1 gJkgthe fourth y- Beginas well as muscular tonus and f r ning with the fourth day, an abnormal state of agitation It consists of suspending mice by the front paws by a is provoked in the treated mice, then in the days followmetallic wire held horizontally. The time necessary for the ing, an irreversible hyperkinetic syndrome, characterized animals to eifect a recovery is noted, that is to say, in by circular running (Waltzing mice) with some retro and order to place at least one of the hind paws on the wire. 75 lateral movements and chorea-athetosic movements of the 7 head. This state is irreversible. These animals are treated comparatively with B.46.65, With Meprobamate and Chlorpromazine and one tests the suppression of this pathologic syndrome.

In the lot of 10 Waltzing mice having received 200 mg./ kg. of B.46.65 intraperitoneally each mouse no longer turns minutes after the injection. A nociceptif stimulus makes them go off again for several seconds, then they stop anew. On an average, they start to turn again spontaneously 1 hr. 9 min. after the injection of B.46.65. In the lot of 10 Waltzing mice that received 100 mg./kg. of B.46.65 intraperitoneally one mouse did not stop turning; the others stopped, on the average, for 10' to 8' after the injection.

In the lot of 10 Waltzing mice having received 100 mg./ kg. of Meprobamate intraperitoneally, no mouse stopped completely but they evidenced rather some periods of tranquillity interrupted by short phases of resumption of activity. On an average, the arrest is produced after 16' and the free resumption of circular movements is produced after 1 hr. 17. However, two mice were practically not arrested.

In the lot of 10 Waltzing mice having received 100 mg./ kg. of Chlorpromazine intraperitoneally all the mice were arrested in an average time of 10' after the injection and the circular movements only resumed after 3 hr. 36.

(B) Antagonism with amphetamine. Effect on the group toxicity An atoxic dose of 30 mg./kg. of amphetamine sulfate, for example, administered in aqueous solution intraperitoneally to mice placed in individual cages can involve an increased mortality if the mice are placed in suflicient number in the same cage. Under the effect of psychic excitation provoked by the product, the grouped mice madden themselves mutually and end by dying of exhaustion and of fear. One has therefore sought to antagonize the effects of amphetamine by administering, /2 hr. before, 200 mg./ kg. of B.46.65 intraperitoneally in oily solution.

The same test, comparatively, is effected with Meprobamate.

The results of this test are summarized in Table IX.

(C) Test of resistance to asphyxia (test of Nassenef) The mice are placed individually in little jam jars closing hermetically and one notes the time at the end of which they die from asphyxia. Under these conditions, one sees that the control animals die more rapidly than those having received a dose of product capable of protecting their nerve cells from the intoxication due to carbon dioxide and to the lack of oxygen. A half hour before the test a lot of animals was treated with 8.46.65 at a dose of 200 mg./kg., intraperitoneally, in oily solution, and another lot with Meprobamate, 200 mg./kg. in the same way, in oily solution.

The results obtained are summarized in Table X.

TABLE X Products, lots of Average time to death 10 mice: by asphyxia Controls 52 B.46.65, 200 mg./kg., I.P. 1 hr. 44'

Meprobamate, 200 mg./kg., I.P 1 hr. 42

(6) Action on experimental restraint to ulceration (A) Ulceration by exertion Rats are put to sleep with ether, then they are immobilized in flexible wire cloth. The four paws are passed through holes cut for this purpose, then attached in pairs with the aid of adhesive tape, so that the animal cannot budge. At the moment of retraint 2.5 ml. of physiologic serum is injected intramuscularly. Under these conditions, in 20 hours all rats developed one or more gastric ulcers accompanied by generally large hemorrhages.

An attempt was made to protect the animals from ulcers or, at least, to lessen it by injecting them intraperitoneally at the start of the experiment with 200 mg./ kg. of B.46.65 in oily solution.

The same test was repeated with Meprobamate in a dose of mg./kg., intraperitoneally, in aqueous solution.

To evaluate the activity of the product the following classification has been adopted: Onormal stomach; l hemorrhagic spots without ulcers; 2one ulcer; 3many ulcers; 4perforation.

Lots of 5 animals have been used. Under these conditions the results obtained are as follows:

TABLE XI 13.46.65, Meprobamate 200 mg./ 100 mg. kg., Controls kg, LP. S.C:

Classification:

(B) Ulcers of electrical constraint The rats are left for 24 hours in a Plexiglas cage the floor of which consists of metal bars receiving an alternating current of an intensity in the area of 40 volts. The bars alternately contact the two poles of current so that the animal only makes contact and receives the current if it puts its paws on two neighboring bars, that is to say on two bars of opposite polarity. After a period of habituation the animals seek a favorable position and then remain perfectly motionless because of fear of receiving an electric discharge.

Under these conditions, all the animals are victims, within 24 hours, of more or less serious alterations of the gastric mucosa. As in the preceding test and at the same doses an attempt has been made to protect the animals by the administration at the time of entry into the cage, of B.46.65 or of Meprobamate.

The results obtained are summarized in Table XII.

TABLE XII 13.46.65, Meprobamatc 200 mg./ 100 mg. kg. Controls kg., LP. S.C.

Classification:

(7) Conclusion of the pharmacological tests B.46.65 possesses interesting pharmacological properties at doses sufficiently remote from toxic doses, which tend to class it as a tranquilizer. It possesses, in effect, at sufficient dose, hypnotic properties and the property of potentiating hypnotic drugs. According to the tests of tranquilizing activity the results obtained are often comparable to those of Meprobamate, frequently superior.

Finally, the results obtained in other tests, notably in the test with iminodipropionitrile, allow a glimpse of certain neuroplegic properties which place the product half way between the minor tranquilizers (Meprobamate type) and the major transquilizers (Chlorpromazine type).

CLINICAL OBSERVATIONS Three additional examples of the applications of the tranquilizing effect of the product of the invention are cited by way of illustration and not limitation.

EXAMPLE III A manual workman, 35 years old, alcoholic for several years, suffering from muscular pains, from slight liver enlargement, from morning phlegm, from insomnia and from irritability receives two pills of 500 mg. at night before bedtime. One observes a resumption of sleep, the disappearance of irritability, the lessening of muscular pains, but no effect on morning phlegm.

EXAMPLE IV A woman of 30 years, married, having acute family problems, and suffering from anxiety, from anguish, from palpitations, from insomnia, from difficulty of falling asleep, receives /2 pill of 500 mg. in the morning, /2 pill of 500 mg. at noon, and one pill of 500 mg. at night before bedtime. One observes a dedramatization of her situation, an improved objectivity, a refreshing sleep and the disappearance of the train of accompanying troubles.

EXAMPLE V- A student of 23 years of age manifests at exam time an increasing anxiety, panic, agitation, trembling and sweating of the extremities, laryngeal constriction, palpitations and insomnia because of anxiety. One has been able to establish a disappearance of these symptoms following a treatment comprising: (1) the first day: /2 pill of 500 mg. in the morning, ditto at noon and ditto at night. (2) The second day: one pill of 500 mg. in the morning and one hour before the examination.

Others may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art of employing one or more of the novel features disclosed or equivalents thereof. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

EXAMPLE VI (A) Compressed tablets of dipropylacetylamino pyrimidine are prepared from a tablet mix containing 400 grams of dipropylacetylamino pyrimidine, 150 grams of microcrystalline cellulose and 50 grams of aluminum stearate. When pressed into tablets weighing 300 milligrams, they provide a dosage of 200 milligrams of the medicinal agent.

(B) A thorough mixture of 800 grams of dipropylacetylamino pyrimidine, 60 grams of talc and 10 grams of magnesium stearate was filled into No. gelatin capsules. The dosage was 400 mg. of the drug per capsule.

(C) Eighty grams of dipropylacetylamino pyrimidine and 20 grams of methylcellulose were stirred into 1 kg. of simple syrup containing 800 mg. of methyl p-hydroxybenzoate and 200 mg. of propyl p-hydroxybenzoate. A stable emulsion was formed. A daily dosage of 1 to 2 ml. of this preparation per os is adequate as a tranquilizers and is adequate for adults.

(D) Suppositories, 2-gram size, were formed from a dispersion of 800 grams of finely powdered dipropylacetylamino pyrimidine in 2 kg. of cocoa butter. Each suppository, administered rectally, provides an adult dosage.

(E) Wafers or tablets, each containing 500 mg. of dipropylacetylamino pyrimidine, can be produced by compounding 100 grams of the medicinal agent with 30 grams of corn starch, grams of magnesium stearate and 10 grams of talc into a tablet mix and pressing 750-mg. tablets or wafers for oral or buccal administration.

We claim:

1. A method of inducing sedation or tranquilization to a warm-blooded animal comprising administering to said animal dipropylacetamido 2 pyrimidine in an amount to induce said sedation and tranquilization.

2. A composition for effecting tranquilization or sedation comprising an effective amount of dipropylacetamido- 2 pyrimidine and a physiologically acceptable carrier 35 therefor.

3. The composition as defined in claim 2 wherein said physiologically acceptable carrier is a tablet.

4. The composition as defined in claim 2 wherein said physiologically acceptable carrier is a fluid suspension.

5. The composition as defined in claim 2 wherein said physiologically acceptable carrier is a capsule.

References Cited UNITED STATES PATENTS 2/ 1959 Traverso et a1. 260256.4N 5/ 1967 Nitta et al 260256.4N 

